Breast cancer is the leading cancer diagnosis and the second highest cause of cancer death in women in the United States. Gene expression analysis has allowed the delineation of different intrinsic subtypes of breast cancer, providing greater prognostic information than standard histologic assessment of ER, PR, and HER2 expression. The intrinsic subtypes include Luminal A, Luminal B, Normal-like, HER2/Neu, Basal-like, and Claudin-low. The most aggressive subtypes, basal-like and claudin-low, have the worst mortality rate of the intrinsic subtypes due to lack of targeted therapy, higher grade at diagnosis, and a predilection for early metastasis. Surprisingly, gene expression profiles from basal-like and claudin-low breast cancer patients demonstrate higher expression of many immune genes, and histologic examination demonstrates high rates of immune cell infiltration into the tumor. However, it remains unclear whether these immune cells are providing an anti-tumor immune response or are promoting tumor growth. The long-term goal of this project is to understand the role of the immune system in basal-like and claudin-low tumor pathogenesis. The goal of this research is to determine whether the immune system is a driver of tumor growth in these aggressive subtypes. Murine tumors of the different intrinsic subtypes, derived from genetically engineered mouse models, mimic the genetic diversity of breast cancers seen in human patients and will provide excellent models for the proposed research. In Aim 1, we will orthotopically implant different tumor models of the intrinsic subtypes and use genetic, biologic, and pharmacologic means to silence or deplete subsets of immune cells that infiltrate the tumor, in order to determine their effect on local tumor growth. In addition, we will disrupt certain chemokine pathways to determine which pathways are critical for the trafficking and infiltration of these immune cells. In Aim 2, we will use genetic and pharmacologic means to disrupt the recruitment of suppressive immune cells and the CXCL12-CXCR4 pathway in order to determine their role in the metastatic potential of basal-like and claudin- low tumors. We hypothesize that specific chemokine pathways are important for the recruitment of immune cells into the tumor, and that increased infiltration by these cells adds to tumor burden and promotes both local growth and metastasis. Identification of chemokine pathways that promote tumor growth and chemokine pathways that promote metastasis are critical for the development of targeted immunotherapies for the treatment of basal-like and claudin-low breast cancers. Further, such targeted immunotherapies, used alone, or as part of a multimodality treatment, may greatly impact the future treatment of patients by aiding in the development of specific immunotherapies for the treatment of patients with these aggressive tumors.